Joseph E. Tota

Epidemiology and burden of HPV infection and related diseases: Implications for prevention strategies

Human papillomavirus (HPV) infection is a necessary, although not sufficient cause of cervical cancer. Globally, HPV infection accounts for an estimated 530,000 cervical cancer cases (~270,000 deaths) annually, with the majority (86% of cases, 88% of deaths) occurring in developing countries. Approximately 90% of anal cancers and a smaller subset (<50%) of other cancers (oropharyngeal, penile, vaginal, vulvar) are also attributed to HPV. In total, HPV accounts for 5.2% of the worldwide cancer burden. HPVs 16 and 18 are responsible for 70% of cervical cancer cases and, especially HPV 16, for a large proportion of other cancers. Prophylactic vaccination targeting these genotypes is therefore expected to have a major impact on the burden of cervical cancer as well as that of other HPV-related cancers. Over the past 50 years, organized or opportunistic screening with Papanicolaou (Pap) cytology has led to major reductions in cervical cancer in most developed countries. However, due to lack of resources or inadequate infrastructure, many countries have failed to reduce cervical cancer mortality through screening. HPV DNA testing recently emerged as a likely candidate to replace Pap cytology for primary screening. It is less prone to human error and more sensitive than Pap in detecting high-grade cervical lesions. For countries with national vaccination programs, HPV testing may also serve as a low cost strategy to monitor long term vaccine efficacy. Introduction of well organized vaccination and screening programs should be a priority for all countries. Increased support from donors is needed to support this cause.

Promising strategies for cervical cancer screening in the post-human papillomavirus vaccination era

Human papillomavirus (HPV) vaccination is expected to reduce the burden of cervical cancer in most settings; however, it is also expected to interfere with the effectiveness of screening. In the future, maintaining Pap cytology as the primary cervical screening test may become too costly. As the prevalence of cervical dysplasias decreases, the positive predictive value of the Pap test will also decrease, and, as a result, more women will be referred for unnecessary diagnostic procedures and follow-up. HPV DNA testing has recently emerged as the most likely candidate to replace cytology for primary screening. It is less prone to human error and much more sensitive than the Pap smear in detecting high-grade cervical lesions. Incorporating this test would improve the overall quality of screening programs and allow spacing out screening tests, while maintaining safety and lowering costs. Although HPV testing is less specific than Pap cytology, this issue could be resolved by reserving the latter for the more labour-efficient task of triaging HPV-positive cases. Because most HPV-positive smears would contain relevant abnormalities, Pap cytology would be expected to perform with sufficient accuracy under these circumstances. HPV Pap triage would also provide a low-cost strategy to monitor long-term vaccine efficacy. Although demonstration projects could start implementing HPV testing as a population screening tool, more research is needed to determine the optimal age to initiate screening, the role of HPV typing and other markers of disease progression, and appropriate follow-up algorithms for HPV-positive and Pap-negative women.

The accuracy of human papillomavirus vaccination status based on adult proxy recall or household immunization records for adolescent females in the United States: results from the National Immunization Survey-Teen

PURPOSE We assessed the accuracy of human papillomavirus (HPV) vaccination status based on adult proxy recall and household immunization records for adolescent females in the United States. METHODS We used data from the 2010 National Immunization Survey-Teen for females aged 13 to 17 years. The accuracy of HPV vaccination status (≥1 dose) based on adult proxy recall (unweighted n = 6868) and household immunization records (unweighted n = 2216) was assessed by estimating the sensitivity, specificity, and corresponding 95% confidence limits (CL) of these measures with provider-reported HPV vaccination status as the reference standard. Our analyses accounted for the complex survey design and population weights. RESULTS The sensitivity and specificity of adult proxy recall were 83.9% (95% CL: 81.2%, 86.6%) and 90.4% (95% CL: 88.9%, 92.0%), respectively. Conversely, the sensitivity and specificity of household immunization records were 74.2% (95% CL: 69.1%, 79.2%) and 98.0% (95% CL: 96.8%, 99.1%), respectively. The accuracy of both measures varied by race/ethnicity, proxy respondent, and maternal education. CONCLUSIONS Our results suggest that adult proxy recall and household immunization records have reasonable accuracy for classifying HPV vaccination status for females aged 13 to 17 years in the United States, but these measures present a trade-off between sensitivity and specificity.

Guillain–Barre syndrome following quadrivalent human papillomavirus vaccination among vaccine-eligible individuals in the United States

Post-marketing surveillance studies provide conflicting evidence about whether Guillain–Barre syndrome occurs more frequently following quadrivalent human papillomavirus (HPV4) vaccination. We aimed to assess whether Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among females and males aged 9 to 26 y in the United States. We used adverse event reports received by the United States Vaccine Adverse Event Reporting System (VAERS) between January 1, 2010 and December 31, 2012 to estimate overall, age-, and sex-specific proportional reporting ratios (PRRs) and corresponding Χ2 values for reports of Guillain–Barre syndrome between 5 and 42 d following HPV vaccination. Minimum criteria for a signal using this approach are 3 or more cases, PRR ≥2, and Χ2 ≥ 4. Guillain–Barre syndrome was listed as an adverse event in 45 of 14 822 reports, of which 9 reports followed HPV4 vaccination and 36 reports followed all other vaccines. The overall, age-, and sex-specific PRR estimates were uniformly below 1. In addition, the overall, age-, and sex-specific Χ2 values were uniformly below 3. Our analysis of post-marketing surveillance data does not suggest that Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among vaccine-eligible females or males in the United States. Our findings may be useful when discussing the risks and benefits of HPV4 vaccination.

Evaluation of Type Replacement Following HPV16/18 Vaccination: Pooled Analysis of Two Randomized Trials.

Background: Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination, type replacement may occur, especially if different HPV types competitively interact during natural infection. Because of their common route of transmission, it is difficult to assess type interactions in observational studies. Our aim was to evaluate type replacement in the setting of HPV vaccine randomized controlled trials (RCTs). Methods: Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT001226810)—two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine—to compare cumulative incidence of nonprotected HPV infections across trial arms after four years. Negative rate difference estimates (rate in control minus vaccine arm) were interpreted as evidence of replacement if the associated 95% confidence interval excluded zero. All statistical tests were two-sided. Results: After applying relevant exclusion criteria, 21 596 women were included in our analysis (HPV arm = 10 750; control arm = 10 846). Incidence rates (per 1000 infection-years) were lower in the HPV arm than in the control arm for grouped nonprotected oncogenic types (rate difference = 1.6, 95% confidence interval [CI] = 0.9 to 2.3) and oncogenic/nononcogenic types (rate difference = 0.2, 95% CI = −0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed. In contrast, a statistically significant protective effect (positive rate difference and 95% CI excluded zero) was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as nononcogenic types 6 and 70. Conclusion: HPV type replacement does not occur among vaccinated individuals within four years and is unlikely to occur in vaccinated populations.

Human Papillomavirus-Associated Subsequent Malignancies among Long-Term Survivors of Pediatric and Young Adult Cancers

Long-term survivors of pediatric and young adult (PAYA) cancers have a high incidence of subsequent neoplasms, but few risk factors other than cancer treatment have been identified. We aimed to describe the burden of human papillomavirus (HPV)-associated malignancies among survivors of PAYA cancers to assess whether HPV infections might be a reasonable area of future etiologic research on subsequent malignancies in this population. We used longitudinal data from 9 population-based registries of the Surveillance, Epidemiology, and End Results program collected between 1973 and 2010 to assemble a cohort of individuals who were diagnosed with any cancer between the ages of 0 and 29 years and survived at least 5 years post-diagnosis. We estimated sex-specific standardized incidence ratios (SIRs) with corresponding 95% confidence limits (CL) of HPV-associated subsequent malignancies (cervical, vaginal, vulvar, penile, anal, tongue, tonsillar, and oropharyngeal). Our study population comprised 64,547 long-term survivors of PAYA cancers diagnosed between 1973 and 2010. Compared with females in the general US population, female PAYA cancer survivors had a 40% relative excess of HPV-associated malignancies overall (SIR = 1.4, 95% CL: 1.2, 1.8). Compared with males in the general US population, male PAYA cancer survivors had a 150% relative excess of HPV-associated malignancies overall (SIR = 2.5, 95% CL: 1.9, 3.4). Our findings suggest an excess of HPV-associated malignancies among PAYA cancer survivors compared with the general US population. We hypothesize that a portion of subsequent malignancies among PAYA cancer survivors may be directly attributable to HPV infection. This hypothesis warrants exploration in future studies.

Approaches for triaging women who test positive for human papillomavirus in cervical cancer screening

Substantial evidence exists to support the introduction of molecular testing for human papillomavirus (HPV) as the primary technology in cervical cancer screening. While HPV testing is much more sensitive than cytology for detection of high-grade precancerous lesions, it is less specific. To improve efficiency, it is therefore recommended that a specific test (like cytology) be used in triaging HPV positive women to colposcopy. A number of studies have been conducted that support the use of cytology alone or in conjunction with HPV genotyping for triage. The decision to incorporate genotyping also depends on the commercial HPV test that is selected since not all tests provide results for certain individual high-risk types. Regardless of whether policy officials decide to adopt a triage approach that incorporates genotyping, the use of liquid based cytology (LBC) may also improve screening performance by reducing diagnostic delays. With LBC, the same cell suspension from a single collection may be used for HPV testing and a smear can be immediately prepared if HPV status is positive. This was a critical lesson from a community based demonstration project in Montreal (VASCAR study), where conventional cytology exists and specimen co-collection was not permitted for ethical reasons, requiring HPV positive women to return for an additional screening visit prior to colposcopy.

Evaluation of Human Papillomavirus Type Replacement Postvaccination Must Account for Diagnostic Artifacts: Masking of HPV52 by HPV16 in Anogenital Specimens

It has been hypothesized that, following a reduction in human papillomavirus (HPV) vaccine–targeted genotypes, an increase in prevalence of other HPV types may occur due to reduced competition during natural infection. Any apparent postvaccination increase must be distinguished from diagnostic artifacts consequent to consensus PCR assays failing to detect HPV types present in low copy numbers in coinfected specimens (under the assumption that with a drop in vaccine-preventable types there may be increased detection of previously “masked” types). We reanalyzed anogenital specimens to evaluate unmasking of HPV52 that may be caused by elimination of HPV16. Using highly sensitive type-specific real-time HPV52 PCR, we retested 1,200 anogenital specimens (all HPV52 negative according to consensus PCR assays) from six epidemiologic studies (200 specimens/study; 100 HPV16+/study). Multivariate logistic regression, with adjustment for age and number of sexual partners, was used to evaluate the association between HPV16 positivity and detection of HPV52. In our pooled analysis (n = 1,196), the presence of HPV16 was positively associated with HPV52 detection [adjusted OR, 1.47; 95% confidence interval (CI), 0.76–2.82]. In our separate (study specific) analyses, a statistically significant association was observed in one study that included HIV-infected males (HIPVIRG study; adjusted OR, 3.82; 95% CI, 1.19–12.26). We observed a positive association between HPV16 viral load (tertiles) and detection of HPV52 (P for trend = 0.003). These results indicate that diagnostic artifacts, resulting from unmasking of HPV52, may occur in some settings in the evaluation of HPV type replacement. Additional studies exploring the extent and severity of unmasking are needed. Cancer Epidemiol Biomarkers Prev; 24(1); 286–90. ©2014 AACR.

Human papillomavirus vaccines: key factors in planning cost-effective vaccination programs.

Prophylactic HPV vaccines hold tremendous potential for reducing cervical and non-cervical HPV-related disease burden worldwide. To maximize on this potential, policy officials will need to carefully consider available evidence, existing uncertainties and the cost–effectiveness of mass HPV vaccination programs in the context of their respective nations and/or regions. Proper harmonization of primary prevention strategies with secondary prevention efforts will also be important. Decisions following such considerations may ultimately depend on programmatic objectives, infrastructure and available resources. Continued research and surveillance surrounding HPV vaccination will be essential for filling current knowledge gaps, and forcing ongoing reconsiderations of selected immunization strategies.

Progress on human papillomavirus (HPV) infection and cervical cancer prevention in sub-Saharan Africa: Highlights of the 27th International Papillomavirus Conference in Berlin, 17–22 September 2011

Highlights of the International Papillomavirus Conference in Berlin, 17–22 September 2011.